Molecular glues are an important novel modality in medicinal chemistry. Blockbuster such as lenalidomide and pomalidomide work on the glue principle by generating a novel interaction between the Ikaros/Aiolos substrate and the E3 ligase cereblon. “Immediate Drop on Demand Technology” (I-DOT) is a nano-dispensing technology and has been mostly applied to analytical and biological questions. This technique could be combined with multicomponent reaction (MCR) to help rapidly build lenalidomide or pomalidomide analogs library. Here, we introduce a practical multicomponent reaction approach to synthesize high diversity pomalidomide analogs employing a one-pot Ugi reaction and Ugi-tetrazole reaction. We prepared 384 different derivatives on a nanoscale in a fully automated fashion by I-DOT. We performed the cell viability screening for the I-DOT synthetic plate and found that many compounds showed better or similar inhibition potency against MM1S cell line compared to the pomalidomide and lenalidomide. Therefore, we selected 19 compounds that showed better inhibition potency and degradation kinetics against MM1S cell line and exemplified the resynthesis on a millimole scale featuring good yield. Finally, we rescreened the resynthesis compound by western blot to testify the degradation of the substrates.<br/>In summary automated high throughput synthesis and screening allows for unprecedented fast molecular glue discovery.

Molecular glue discovery by high throughput nL chemistry

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.